Digital imaging techniques for assessing the precise location and extent of disease burden in overt atherosclerotic CVD include computed tomography and magnetic resonance (MR) for directly imaging of atherosclerotic plaques and determining structure and biochemical make-up of the lesions. However, the tools available for detecting the earliest presymptomatic changes, brought about by endothelial dysfunction (EDF), are unsatisfactory. This gap is of particular concern as a reproducible, accurate, noninvasive technique for quantifying measures of these earliest stages of pathogenesis would allow preventive intervention well before the onset of symptoms, thus reducing morbidity and mortality, and curbing healthcare costs. A key hallmark of EDF is impaired vascular reactivity in response to increased shear stress or increased demand for oxygen delivery. All current methods for assessing vascular reactivity, typically based on ultrasound, have significant limitations in both precision and sensitivity. The objective of the proposed research is to develop, implement and evaluate a new MRI-based approach for quantifying vascular reactivity to detect early signs of functional deficits. Toward such a goal the investigators have, in preliminary work, conceived and implemented an integrated quantitative MRI protocol for noninvasively assessing endothelial function, as part of a single one-hour examination. Key elements of the protocol comprise high-speed projection mapping of time-resolved femoral artery velocity at baseline and during hyperemia, simultaneously with a method for quantifying the dynamics of venous blood oxygen resaturation during hyperemia, and a technique for efficient quantification of arterial pulse wave velocity from central to peripheral conduit arteries. We conjecture that, individually and collectively, the MRI-derived parameters vary both in an age- and lifestyle-dependent manner across two age groups of subjects, each partitioned into smokers and non- smokers, who will be evaluated at baseline and two years thereafter. We hypothesize that each time-point, (i) older subjects will have lower vascular performance than their younger peers, (ii) a similar relationship holds for smokers relative to their nonsmoking peers, and (iii) the decline in the physiologic parameters will be greater in smokers in either age group at the end of a two-year observation period, and (iv) the MRI parameters measured parallel those obtained by ultrasound but that, collectively, they are stronger group differentiators and are more sensitive to expected longitudinal changes. These hypotheses will be addressed in three specific aims designed to further develop, integrate and evaluate the performance of the method and apply it in an observational pilot study to a cohort of healthy men. The integration, evaluation and translation to the clinic of the proposed methodology is likely to yield more effective tools for noninvasive evaluation of subjects at risk of developing cardiovascular disease and to provide a basis for future large-scale intervention trials. PUBLIC HEALTH RELEVANCE: Cardiovascular disease (CVD) is the main cause of death and morbidity in the industrialized world. While significant advances have been made in diagnosis and treatment of CVD, patients diagnosed are often at a late stage of disease progression. This project proposes to develop and translate to the clinic novel imaging methodology that enable diagnosis of the earliest stages of disease thereby allowing for lifestyle changes and early intervention in subjects at risk.